Activation of Intrinsic Immune Responses and Microglial Phagocytosis in an
            <i>Ex Vivo</i>
            Spinal Cord Slice Culture Model of West Nile Virus Infection

Quick, Eamon D.; Leser, J. Smith; Clarke, Penny; Tyler, Kenneth L.

doi:10.1128/jvi.01994-14

Cited by 66 publications

(81 citation statements)

References 72 publications

(90 reference statements)

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“…Iba-1 (ionized calcium-binding adapter molecule 1) is frequently used, but cannot distinguish microglia from macrophages in vivo, although it can be helpful in conjunction with an amoeboid shape of the cell, with pronounced processes more consistent with microglia (Patro et al, 2013;Quick et al, 2014). In vitro studies with isolated microglia are also of limited utility as much of microglial function is dependent on interaction with surrounding cell types.…”

Section: Microgliamentioning

confidence: 99%

Neuroglia in Infectious Brain Diseases

Skar¹

2015

Colloquium Series on Neuroglia in Biology and Medicine: From Physiology to Disease

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Section: Microgliamentioning

confidence: 99%

Neuroglia in Infectious Brain Diseases

Skar¹

2015

Colloquium Series on Neuroglia in Biology and Medicine: From Physiology to Disease

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“…CXCL10, CXCL1, CCL5, CCL3, and CCL2) and cytokines (e.g. TNFα, TRAIL and IL6) were upregulated during microglial cell activation [149]. These responses are also observed in in vitro infected microglial cells [151].…”

Section: Macrophages/monocytesmentioning

confidence: 48%

“…However, there is conflicting evidence as to whether these monocytes provide protection or cause immunopathology [147,148]. In particular, deficiency of CC chemokine receptor (CCR)-2 on monocytes [147] played an important role in phagocytosis of WNV-infected neurons and astrocytes [149]. Several chemokines (e.g.…”

Section: Macrophages/monocytesmentioning

confidence: 99%

“…In the CNS, the role of neurons and astrocytes in WNV restriction has been investigated extensively in vitro [53,64,[149][150][151][192][193][194]. In modelling the responses of neurons to WNV infection, in vitro WNV-infection of neurons (human neuroblastoma cell line, SK-N-SH) have been shown to result in their expression of a range of pro-inflammatory cytokines, such as IL1β, IL6, IL8 and TNFα [64].…”

Section: Non-leukocytic Cellsmentioning

confidence: 99%

“…Non-leukocytic cells, such as fibroblasts, epithelial and neural cells, contribute to the early detection and mediation of cytokine and chemokine expression, as part of the antiviral defence mechanisms [53,64,[149][150][151][190][191][192][193][194]. In the skin of WNV-infected 6 week-old C3H mice, cells within the epidermis and adnexal glands (likely keratinocytes) were identified as targets for WNV replication, and may contribute to the persistence of virus in the skin, due to the slow turnover rate of keratinocytes (~ every 52 to 75 days for humans) [195].…”

Section: Non-leukocytic Cellsmentioning

confidence: 99%

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Investigation of neuropathogenesis and control of an equine-pathogenic Australian West Nile virus isolate in an established CD1 Swiss white mouse and a novel rabbit model

Suen¹

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West Nile virus (WNV) is a globally significant mosquito-borne neurotropic virus. In 2011, a large-scale arboviral encephalitis outbreak occurred in Australia, involving close to 1000 horses. A virulent WNV strain, WNV NSW2011 , was isolated from the brain of an encephalitic horse during this outbreak. Preliminary assessment showed that this strain is intermediate in virulence and belongs in the same lineage as the highly virulent North American strains. However, the pathogenesis of WNV in general, let alone this novel Australian strain, remains largely unclear.The first part of the project aimed to investigate the pathogenesis of lethal WNV NSW2011 infection in the established young adult Swiss white (CD1) mouse model, since previous survival challenge experiments demonstrated high lethality (~70%) of WNV NSW2011 in this animal model. I conducted a pilot time-course experiment, which demonstrated only benign pathological and virological outcomes in sacrificed mice on day 3 and 7 post-infection (pi), despite the relatively high lethality seen in previous survival trials. In a subsequent experiment, I characterised the disease phenotype in moribund/dead and surviving mice after WNV NSW2011 infection. Notably, I detected a high degree of intra-group variability in the neuropathology, neural infection and glial cell activation. Even cases with neuroinvasion are typically not fatal, unless underlying co-morbidities or immunosuppressive disease exist.I chose rabbits as a candidate for a novel animal model, due to the ease of performing intra-vital sampling and monitoring, as well as the possibility for tissue sharing in different assays, given the larger size of rabbits than mice. Rabbits are also hind-gut fermenters, and thus may be a better representation of a horse than a mouse. New Zealand White (NZWRs; Oryctolagus cuniculus) and iii North American cottontail rabbits (CTRs; Sylvilagus sp.) were challenged with WNV strains of different virulence (WNV NSW2011 and WNV TX8667 ), and the prototype Murray Valley encephalitis virus strain (MVE 1-51 ), by the footpad route. The rabbits were consistently resistant to developing severe disease after virulent WNV and MVEV infection, regardless of age, gender and species, despite productive virus replication in the draining popliteal lymph node (PLN). The resultant viraemia for all rabbits was also of low magnitude and transient. Furthermore, establishment of virus infection in the brain was not a feature of the disease, despite mild to moderate neuropathology in a subset of rabbits. This capacity to control flavivirus infection may be explained by the rapid antiviral innate immune response detectable by day 3 pi, as well as a fast anti-WNV neutralising antibody response detectable from day 7 pi.Comparisons of the tissue-specific transcriptional profile of important cytokine and chemokine genes suggested that virus control in rabbits was achieved differently depending on the virus, as well as the rabbit species. However, common transcriptional upregulation of IFNγ in...

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Activation of neurotoxic A1‐reactive astrocytes by SFTS virus infection accelerates fatal brain damage in IFNAR1^‐/‐ mice

Kim,

Choi,

et al. 2024

Journal of Medical Virology

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Severe fever with thrombocytopenia syndrome (SFTS) has a high mortality rate compared to other infectious diseases. SFTS is particularly associated with a high risk of mortality in immunocompromised individuals, while most patients who die of SFTS exhibit symptoms of severe encephalitis before death. However, the region of brain damage and mechanisms by which the SFTS virus (SFTSV) causes encephalitis remains unknown. Here, we revealed that SFTSV infects the brainstem and spinal cord, which are regions of the brain associated with respiratory function, and motor nerves in IFNAR1‐/‐ mice. Further, we show that A1‐reactive astrocytes are activated, causing nerve cell death, in infected mice. Primary astrocytes of SFTSV‐infected IFNAR1‐/‐ mice also induced neuronal cell death through the activation of A1‐reactive astrocytes. Herein, we showed that SFTSV induces fatal neuroinflammation in the brain regions important for respiratory function and motor nerve, which may underlie mortality in SFTS patients. This study provides new insights for the treatment of SFTS, for which there is currently no therapeutic approach.

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Activation of Intrinsic Immune Responses and Microglial Phagocytosis in an Ex Vivo Spinal Cord Slice Culture Model of West Nile Virus Infection

Abstract: West Nile virus (WNV) is a neurotropic flavivirus that causes

Cited by 66 publications

References 72 publications

Neuroglia in Infectious Brain Diseases

Neuroglia in Infectious Brain Diseases

Investigation of neuropathogenesis and control of an equine-pathogenic Australian West Nile virus isolate in an established CD1 Swiss white mouse and a novel rabbit model

Activation of neurotoxic A1‐reactive astrocytes by SFTS virus infection accelerates fatal brain damage in IFNAR1^‐/‐ mice

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Activation of Intrinsic Immune Responses and Microglial Phagocytosis in an Ex Vivo Spinal Cord Slice Culture Model of West Nile Virus Infection

Abstract: West Nile virus (WNV) is a neurotropic flavivirus that causes

Cited by 66 publications

References 72 publications

Neuroglia in Infectious Brain Diseases

Neuroglia in Infectious Brain Diseases

Investigation of neuropathogenesis and control of an equine-pathogenic Australian West Nile virus isolate in an established CD1 Swiss white mouse and a novel rabbit model

Activation of neurotoxic A1‐reactive astrocytes by SFTS virus infection accelerates fatal brain damage in IFNAR1‐/‐ mice

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Product

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Activation of neurotoxic A1‐reactive astrocytes by SFTS virus infection accelerates fatal brain damage in IFNAR1^‐/‐ mice